Leukocyte-mediated production of eicosanoids in rat lungs: modulation by a calcium antagonist

Abstract

Formyl peptide (fMLP) by itself does not increase eicosanoid levels in rat lungs, but eicosanoid levels and edema do increase if endotoxin (ETX) is given before an fMLP challenge. The role of pulmonary intravascular leukocytes in fMLP-induced eicosanoid production in rat lungs was studied, as was the effect of a calcium antagonist (Ro 40-5967). ETX increased the levels of 6-keto PGF1 alpha, but not the levels of TXB2 or LTB4. A second challenge with fMLP in ETX-primed rats resulted in increased production of these three eicosanoids, and increased neutrophil accumulation, as assessed by myeloperoxidase assay. The calcium antagonist attenuated both the production of eicosanoids and the accumulation of neutrophils in the lung. The levels of both 6-keto PGF1 alpha and TXB2 correlated well with lung neutrophil accumulation. Leukocytes isolated from the pulmonary vasculature released TXB2 and LTB4 when stimulated with fMLP in vitro. The amount of these eicosanoids released from pulmonary intravascular leukocyte suspension was well correlated with neutrophil counts in a leukocyte suspension. These data indicate that fMLP-induced production of eicosanoids in the lung, especially production of TXB2, is mediated by pulmonary intravascular neutrophils, and that calcium antagonists can attenuate eicosanoid production by decreasing the accumulation of neutrophils in the lung.